Medical advances over the last century have enabled people to live longer and remain healthy for a significantly greater amount of time. It is critical that clinicians understand the changes that occur in various organ systems with aging if we are to achieve improvements in the care of the elderly patient. Significant alterations occur in the gastrointestinal (Gl) tract with aging, which can manifest as impairments in physiologic functions, such as alterations in growth, secretion, motility, and response to trophic factors. These changes have direct ramifications to diseases that are more common in the elderly, such as the development of Gl malignancies. Relatively few studies have rigorously examined the changes that occur in the Gl tract and pancreas with aging. With the support of this grant, our laboratory has made great strides in the better understanding of the physiologic changes that occur in the Gl tract with aging. We have identified important functional alterations that occur with age, such as dysregulation of pancreatic growth and function. Our studies have shown that aging affects Gl hormones and their target tissues. Recently, we have identified an important role for the phosphatidylinositol-3 kinase (PI3K) pathway in normal pancreatic proliferation; decreased PI3K/Akt activity is noted in the pancreas with aging, which is associated with decreased proliferative capacity. Based on our findings, the central hypothesis of this project is that aging results in a decreased proliferative capacity of the pancreas. Moreover, we postulate that a reduction in the activity of the PI3K/Akt signaling pathway contributes to the age-related changes possibly mediated by alteration in insulin-like growth factor-1 (IGF-1) expression or cell responsiveness to IGF-1. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) To determine the role of the PI3K/Akt pathway in the age-associated alteration of pancreatic growth. 2) To elucidate the role of IGF-1 and its receptor on altered PI3K/Akt expression and proliferation. 3) To further delineate alterations in the PI3K/Akt signaling pathway and upstream effector proteins in isolated acinar cells from young and aged pancreas. Our studies, utilizing novel in vivo and in vitro models, will continue to challenge previous concepts and viewpoints regarding the aging process. Finally, in collaboration with the other projects and cores in the Program Project Grant, our studies will continue to address clinically relevant questions of Gl health and disease with aging, which will translate to a better understanding of the effects of aging on the Gl tract and possibly lead to novel therapies.